This invention relates to certain dihydropyridines, specifically to certain 1,4-dihydropyridines having a hydroxy or oxo-substituted heterocyclic ring in a side chain attached to the 2-position, which have utility as anti-ischaemic and antihypertensive agents, and to pharmaceutical preparations containing such compounds.
The compounds of the invention reduce the movement of calcium into the cell and they are thus able to delay or prevent the cardiac contracture which is believed to be caused by an accumulation of intracellular calcium under ischaemic conditions. Excessive calcium influx during ischaemia can have a number of additional adverse effects which would further compromise the ischaemic myocardium. These include less efficient use of oxygen for ATP production, activation of mitochondrial fatty acid oxidation and possibly, promotion of cell necrosis. Thus the compounds are useful in the treatment or prevention of a variety of cardiac conditions, such as angina pectoris, cardiac arrythmias, heart attacks and cardiac hypertrophy. The compounds also have vasodilator activity since they can inhibit calcium influx in cells of vascular tissue and they are thus also useful as antihypertensive agents and for the treatment of coronary vasospasm.
According to the specification of our European Patent Application No. 60674 there are described and claimed a number of dihydropyridine anti-ischaemic and antihypertensive agents wherein the 2-position of the dihydropyridine ring is substituted with certain N,N-disubstituted-aminoalkoxymethyl groups. Our co-pending European patent application No. 100189 describes and claims a related series of compounds wherein the 2-position is substituted with an aromatic heterocyclylalkoxymethyl group. We have now discovered a further series of dihydropyridine compounds having valuable therapeutic properties wherein the 2-position substituent bears a hydroxy- or oxo-substituted heterocyclic group.
Thus according to the invention, there are provided novel 1,4-dihydropyridine derivatives of the formula: ##STR2## and their pharmaceutically acceptable salts; wherein
R is aryl or heteroaryl; PA0 R.sup.1 and R.sup.2 are each independently C.sub.1 -C.sub.4 alkyl or 2-methoxyethyl; PA0 X is a 5 or 6 membered nitrogen-containing heterocyclic ring which is substituted with one or more hydroxyl or oxo groups and which may optionally be fused to a further 5 or 6 membered nitrogen-containing heterocyclic ring, and which may optionally be additionally substituted in the heterocyclic ring or further fused heterocyclic ring by one or more C.sub.1 -C.sub.4 alkyl, phenyl, CN, N(R.sup.3).sub.2, (CH.sub.2).sub.m CO.sub.2 R.sup.3 or (CH.sub.2).sub.m CON(R.sup.3).sub.2 groups, wherein each R.sup.3 is independently H or C.sub.1 -C.sub.4 alkyl or the two groups R.sup.3 are taken together with the nitrogen atom to which they are attached to form a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(C.sub.1 -C.sub.4 alkyl)-piperazinyl group, and m is 0 or 1; Y is --(CH.sub.2).sub.n --, --CH.sub.2 CH(CH.sub.3)-- or --CH.sub.2 C(CH.sub.3).sub.2 --; and PA0 n is 1 to 3 when X is linked to Y by a ring carbon atom, or 2 or 3 when X is linked to Y by a ring nitrogen atom. PA0 2-Amino-1-{2-&lt;[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6- methyl-1,4-dihydropyridin-2-yl]methoxy&gt;ethyl}-4-imidazolone; PA0 1-{2-&lt;[4-(2,3-Dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1 ,4-dihydropyridin-2-yl]methoxy&gt;ethyl}imidazolidine-2,4-dione; PA0 4-Amino-1-{2-&lt;[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6- methyl-1,4-dihydropyridin-2-yl]methoxy&gt;ethyl}-2-imidazolone; PA0 2-{2-&lt;[4-(2,3-Dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1 ,4-dihydropyridin-2-yl]methoxy&gt;ethyl}-1-oxo-1,3-dihydropyrrolo[2,3-b]pyridi ne; PA0 6-{[4-(2,3-Dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4- dihydropyridin-2-yl]methoxymethyl}-2,3dimethyl-4-pyrimidone, and PA0 2-Amino-6-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-met hyl-1,4-dihydropyridin-2-yl]methoxymethyl}-4-pyrimidone
The pharmaceutically acceptable acid addition salts of the compounds of the formula (I) are those formed from acids which form non-toxic acid addition salts, for example the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate and tartrate salts. For compounds with an acidic substituent salts may also be formed with bases, examples are the sodium, potassium and ammonium salts.
The term "aryl" as used in this specification for R, includes phenyl and phenyl substituted by one or two substituents each independently selected from nitro, halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, trifluoromethyl and cyano. It also includes 1- and 2-naphthyl.
The term "heteroaryl" as used in this specification for R means an aromatic heterocyclic group which may optionally be substituted and includes, for example, benzofuranyl; benzothienyl; pyridyl optionally substituted by methyl, methylthio, cyano or halo; quinolyl; benzoxazolyl; benzothiazolyl; furyl; pyrimidinyl; thiazolyl; 2,1,3-benzoxadiazol-4-yl; 2,1,3-benzothiadiazol-4-yl; and thienyl optionally monosubstituted by halo or C.sub.1 -C.sub.4 alkyl.
The 5 or 6 membered nitrogen-containing heterocyclic ring X may contain from one to three nitrogen atoms in the ring and may be saturated or unsaturated. As will be understood by those skilled in the art the hydroxyl- or oxo-substituted heterocyclic rings can be subject to keto-enol tautomerism and the group may be present either as a free hydroxyl group when in the tautomeric enol form, or as an oxo group when in the keto form. Which particular isomer is present in normal circumstances can be readily determined by appropriate physical measurements, such as for example by infra-red spectroscopy, and, in some instances the compounds may exist as mixtures of the two forms. However it is to be understood that the invention includes both forms of the compounds where they can exist and, in the description and Examples hereto, references to the hydroxy or keto form of the compound include all possible tautomeric forms and are not necessarily to be taken to indicate which is the predominant tautomeric form of the compound.
The ring X may be linked to the group Y either by a ring carbon or a ring nitrogen atom, with the proviso that, if X is linked by a ring nitrogen atom, Y must contain at least two carbon atoms (i.e. n is 2 or 3).
Examples of suitable heterocyclic rings include 2-,4- and 5-imidazolone, 3-pyrazolone, pyrroline-2,5-dione, imidazolidine-2,4-dione, 2-pyridone, 3-piperazinone, 4-pyrimidone, pyrimidine-2,4-dione, 5-hydroxy-(1H)-1,2,3-triazole and 1-oxo-1,3-dihydropyrrolo[2,3b]pyridine.
The heterocyclic ring X may contain further substituents. Preferred substituent groups are amino, lower alkyl, particularly methyl, carbamoyl and CN. Thus particular and preferred examples of X include 1-(2-amino-4-imidazolone), 1-(imidazolidine-2,4-dione), 1-(4-amino-2-imidazolone), 2-(1-oxo-1,3-dihydropyrrolo[2,3b]pyridine), 6-(2-amino-4-pyrimidone) and 6-(2,3-dimethyl-4-pyrimidone).
The term "halo" means fluoro, chloro, bromo or iodo. Alkyl and alkoxy groups having 3 or more carbon atoms can be straight or branched chain. Compounds containing asymmetric centres will exist as one or more pairs of enantiomers and the invention includes the separated d- and l-optically active isomers as well as mixtures thereof.
Preferred values for R are 2-chlorophenyl and 2,3-dichlorophenyl. R.sup.1 and R.sup.2 are preferably CH.sub.3 or C.sub.2 H.sub.5 ; the case where R.sup.1 is CH.sub.3 and R.sup.2 is C.sub.2 H.sub.5 being especially preferred. Y is preferably --(CH.sub.2).sub.2 -- when X is linked to Y by a ring nitrogen atom, or --CH.sub.2 -- when X is linked to Y by a ring carbon atom. Thus particular and preferred examples of compounds of the invention include the following:
the latter compound being particularly preferred as having especially favourable properties.